Natural transmission of HIV-1 is typically by viruses that use CCR5 as a coreceptor (R5 viruses). Individuals who lack a functional CCR5 gene are strongly resistant to HIV-1 infection, yet have no apparent health problems from their CCR5-negative status. This suggests that targeting CCR5 with, for example, topical microbicides, could safely and significantly reduce the natural transmission of HIV-1. Accordingly, our central hypothesis for this PO1 program Project proposal will be that a carrier matrix containing a CCR5 ligand will provide an effective biological barrier against vaginal HIV transmission. Development and testing treatments based on this hypothesis would be greatly facilitated by the availability of a suitable animal model for infection by R5 viruses. We propose developing an R5 SHIV that can be transmitted mucosally in macaques, using the env, tat, rev and vpu genes from HIV-1 (Ba-L), a prototypic R5 HIV-1. This virus will then be used to test the efficacy in prevention the transmission of SHIV (Ba-L) of either or both of two topical microbicides developed under Project 1 and Project 2 of this program.